Unresectable Stage III, Stage IV, and Recurrent Melanoma Treatment
Treatment Options for Unresectable Stage III, Stage IV, and Recurrent Melanoma
Signal transduction inhibitors
Palliative local therapy
Treatment Options Under Clinical Evaluation for Unresectable Stage III, Stage IV, and Recurrent Melanoma
Current Clinical Trials
Treatment Options for Unresectable Stage III, Stage IV, and Recurrent Melanoma
- Signal transduction inhibitors.
- BRAF (V-raf murine sarcoma viral oncogene homolog B1) inhibitors (for patients who test positive for the BRAF V600 mutation).
- MEK inhibitors.
- Combination therapy with signal transduction inhibitors.
- Dabrafenib plus trametinib.
- Multikinase inhibitors.
- KIT inhibitors.
- Palliative local therapy.
Although melanoma that has spread to distant sites is rarely curable, treatment options are rapidly expanding. Two approaches—checkpoint inhibition and targeting the mitogen-activated protein kinase (MAPK) pathway—have demonstrated improvement in overall survival in randomized trials versus the use of dacarbazine (DTIC) or in comparison to DTIC. Although none appear to be curative when used as single agents, early data of combinations are promising. Given the rapid development of new agents and combinations, patients and their physicians are encouraged to consider treatment in a clinical trial for initial treatment and at the time of progression.Immunotherapy
Ipilimumab is a human monoclonal antibody that binds to CTLA-4, thereby blocking its ability to down-regulate T-cell activation, proliferation, and effector function.
Ipilimumab has demonstrated clinical benefit by prolonging OS in randomized trials, and was approved by the U.S. Food and Drug Administration (FDA) in 2011. Two prospective, randomized, international trials, one each in previously untreated and treated patients, supported the use of ipilimumab.[1,2]
- Previously treated patients: A total of 676 patients with previously treated, unresectable stage III or stage IV disease, and who were HLA-A*0201 positive, were entered into a three-arm, multinational, randomized (3:1:1), double-blind, double-dummy trial. A total of 403 patients were randomly assigned to receive ipilimumab (3 mg/kg every 3 weeks for 4 doses) with glycoprotein 100 (gp100) peptide vaccine. One hundred thirty-seven patients received ipilimumab (3 mg/kg every 3 weeks for 4 doses), and 136 patients received the gp100 vaccine. Patients were stratified by baseline metastases and prior receipt or nonreceipt of interleukin-2 (IL-2) therapy. Eighty-two of the patients had metastases to the brain at baseline.[Level of evidence: 1iA]
- The median OS was 10 months among patients receiving ipilimumab alone and 10.1 months among those receiving ipilimumab with the gp100 vaccine, compared with 6.4 months for patients receiving the vaccine alone (hazard ratio [HR] of ipilimumab alone vs. gp100 alone, 0.66; P <.003; HR of ipilimumab plus vaccine vs. gp100 alone, 0.68; P < .001).
- An analysis at 1 year showed that among patients treated with ipilimumab, 44% of those treated with ipilimumab and 45% of those treated with ipilimumab and the vaccine were alive, compared with 25% of the patients who received the vaccine only.
- Grade 3 or grade 4 immune-related adverse events occurred in 10% to 15% of patients treated with ipilimumab. These immune-related adverse events most often included diarrhea or colitis, and endocrine-related events (e.g., inflammation of the pituitary). These events required cessation of therapy and institution of anti-inflammatory agents such as corticosteroids or, in four cases, infliximab (an antitumor necrosis factor-alpha antibody).
- There were 14 drug-related deaths (2.1%), and seven deaths were associated with immune-related adverse events.
- Previously untreated patients: A multicenter, international trial randomly assigned 502 patients untreated for metastatic disease (adjuvant treatment was allowed) in a 1:1 ratio to receive ipilimumab (10 mg/kg) plus DTIC (850 mg/m2) or placebo plus DTIC (850 mg/m2) at weeks 1, 4, 7, and 10 followed by DTIC alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary endpoint was survival. Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic stage. Approximately 70% of the patients had an ECOG PS of 0, and the remainder of the patients had an ECOG PS of 1. Approximately 55% of patients had stage M1c disease.[Level of evidence: 1iA]
- The median OS was 11.2 months (95% confidence interval [CI], 9.4–13.6) for the ipilimumab-DTIC group, versus 9.1 months (95% CI, 7.8–10.5) for the placebo-DTIC group. Estimated survival rates in the ipilimumab-DTIC group were 47.3% at 1 year, 28.5% at 2 years, and 20.8% at 3 years (HR for death, 0.72; P < .001); and in the placebo-DTIC group, the rates were 36.3% at 1 year, 17.9% at 2 years, and 12.2% at 3 years.
- The most common study-drug–related adverse events were those classified as immune related. Grade 3 or grade 4 immune-related adverse events were seen in 38.1% of patients treated with ipilimumab plus DTIC versus 4.4% of patients treated with placebo plus DTIC, the most common events were hepatitis and enterocolitis.
- No drug-related deaths occurred.
Clinicians and patients should be aware that immune-mediated adverse reactions may be severe or fatal. Early identification and treatment, including potential administration of systemic glucocorticoids or other immunosuppressants according to the immune-mediated adverse reaction management guide provided by the manufacturer, are necessary.Anti–PD-1 and PD-L1
The PD-1 pathway is a key immunoinhibitory mediator of T-cell exhaustion. Blockade of this pathway can lead to T-cell activation, expansion, and enhanced effector functions. PD-1 has 2 ligands, PD-L1 and PD-L2 (Programmed Death-2 Ligand 2).
Anti–PD-1, a human monoclonal antibody directed against PD-1, prevents PD-1 from binding to its ligands. Anti-PD-L1, a human monoclonal antibody directed against PD-L1, prevents PD-L1 from binding and activating its receptor, PD-1.
Promising early data have supported testing several anti–PD-1 antibodies in phase III trials as single agents [4,5] and in combination with ipilimumab  against standard therapy (NCT01844505 and NCT01866319).High-dose interleukin-2 (IL-2)
IL-2 was approved by the FDA in 1998 on the basis of durable complete responses (CRs) in eight phase I and II studies. Phase III trials comparing high-dose IL-2 to other retreatments, providing an assessment of relative impact on OS, have not been conducted.
Evidence (high-dose IL-2):
- Based on a pooled analysis of 270 patients from eight single- and multi-institutional trials in 22 institutions conducted between 1985 and 1993:
- High-dose IL-2 demonstrated a 6% to 7% CR rate.
- With a median follow-up time for surviving patients of at least 7 years, the median duration of CRs was not reached but was at least 59 months.
Strategies to improve this therapy are an active area of investigation.Dual immunomodulation
T-cells coexpress several receptors that inhibit T-cell function. Preclinical data and early clinical data suggest that coblockade of the two inhibitory receptors, CTLA-4 and PD-1, may be more effective than blockade of either alone. This has led to a phase III trial comparing each single agent to the combination (NCT01844505).Signal transduction inhibitors
Studies to date indicate that both BRAF and MEK (mitogen-activated ERK-[extracellular signal-regulated kinase] activating kinase) inhibitors, as single agents and in combination, can significantly impact the natural history of melanoma, although they do not appear to provide a cure.BRAF inhibitors
Vemurafenib is an orally available, small molecule, selective BRAF kinase inhibitor that was approved by the FDA in 2011 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation.
Treatment with vemurafenib is discouraged in wild-type BRAF melanoma because data from preclinical models have demonstrated that BRAF inhibitors can enhance rather than down-regulate the MAPK pathway in tumor cells with wild-type BRAF and upstream RAS mutations.[9-12]
- Previously untreated patients: The approval of vemurafenib was supported by an international, multicenter trial (BRIM-3 [NCT01006980]) that screened 2,107 patients with previously untreated stage IIIC or IV melanoma for the BRAF V600 mutation and identified 675 patients via the cobas 4800 BRAF V600 Mutation Test. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or DTIC (1,000 mg/m2 intravenously [IV] every 3 weeks). Coprimary endpoints were rates of OS and progression-free survival (PFS). At the planned interim analysis, the Data and Safety Monitoring Board determined that both the OS and PFS endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib and recommended that patients in the DTIC group be allowed to cross over to receive vemurafenib.[Levels of evidence: 1iiA and 1iiDiii]
- A total of 675 patients were evaluated for OS; although the median survival had not yet been reached for vemurafenib and the data were immature for reliable Kaplan-Meier estimates of survival curves, the OS in the vemurafenib arm was clearly superior to that in the DTIC arm.
- The HR for death in the vemurafenib group was 0.37 (95% CI, 0.26–0.55; P < .001). The survival benefit in the vemurafenib group was observed in each prespecified subgroup, for example, age, sex, ECOG PS, tumor stage, lactic dehydrogenase, and geographic region.
- The HR for tumor progression in the vemurafenib arm was 0.26 (95% CI, 0.20–0.33; P < .001). The estimated median PFS was 5.3 months in the vemurafenib arm versus 1.6 months in the DTIC arm.
- Twenty patients had non-BRAF V600E mutations: 19 with BRAF V600K and 1 with BRAF V600D. Four patients with a BRAF V600K mutation had a response to vemurafenib.
- Adverse events required dose modification or interruption in 38% of patients receiving vemurafenib and 16% of those receiving DTIC. The most common adverse events with vemurafenib were cutaneous events (i.e., arthralgia and fatigue). Cutaneous squamous cell carcinoma (SCC), keratoacanthoma, or both developed in 18% of patients and were treated by simple excision. The most common adverse events with DTIC were fatigue, nausea, vomiting, and neutropenia. (Refer to the PDQ summaries on Supportive and Palliative Care for more information on coping with cancer.)
- Previously treated patients: A total of 132 patients with a BRAF V600E or BRAF V600K mutation were enrolled in a multicenter phase II trial of vemurafenib, which was administered as 960 mg orally twice daily. Of the enrolled patients, 61% had stage M1c disease, and 49% had an elevated lactate dehydrogenase level. All patients had received one or more prior therapies for advanced disease. Median follow-up was 12.9 months.[Level of evidence: 3iiiDiv]
- An independent review committee (IRC) reported a 53% response rate (95% CI, 44–62), with eight patients (6%) achieving CR.
- Median duration of response per IRC assessment was 6.7 months (95% CI, 5.6–8.6). Most responses were evident at the first radiologic assessment at 6 weeks; however, some patients did not respond until after receiving therapy for more than 6 months.
Dabrafenib is an orally available, small molecule, selective BRAF inhibitor that was approved by the FDA in 2013 for patients with unresectable or metastatic melanoma who test positive for the BRAF V600E mutation as detected by an FDA-approved test. Dabrafenib and other BRAF inhibitors are not recommended for treatment of BRAF wild type melanomas, as in vitro experiments suggest there may be a paradoxical stimulation of MAPK signaling resulting in tumor promotion.
- An international, multicenter trial (BREAK-3 [NCT01227889]) compared dabrafenib with DTIC. A total of 250 patients with unresectable stage III or IV melanoma and BRAF V600E mutations were randomly assigned in a 3:1 ratio (dabrafenib 150 mg orally twice a day or DTIC 1,000 mg/m2 IV every 3 weeks). IL-2 was allowed as prior treatment for advanced disease. The primary endpoint was PFS; patients could cross over at the time of progressive disease after confirmation by a blinded IRC.[Level of Evidence: 1iiDiii]
- With 126 events, the HR for PFS was 0.30 (95% CI, 0.18–0.51; P < .0001). The estimated median PFS was 5.1 months for dabrafenib versus 2.7 months for DTIC. OS data are limited by the median duration of follow-up and crossover. Partial response was 47% versus 5%, and CR was 3% versus 2% in patients receiving dabrafenib versus DTIC, respectively.
- The most frequent adverse events in patients treated with dabrafenib were cutaneous findings (i.e., hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Cutaneous SCC or keratoacanthoma occurred in 12 patients, basal cell carcinoma occurred in four patients, mycosis fungoides occurred in one patient, and new melanoma occurred in two patients.
Trametinib is an orally available, small-molecule, selective inhibitor of MEK1 and MEK2. BRAF activates MEK1 and MEK2 proteins, which in turn, activate MAP kinases. Preclinical data suggest that MEK inhibitors can restrain growth and induce cell death of some BRAF-mutated human melanoma tumors. BRAF activates MEK1 and MEK2 proteins, which, in turn, activate MAPK.
In 2013, trametinib was approved by the FDA for patients with unresectable or metastatic melanoma with BRAF V600E or K mutations, as determined by an FDA-approved test.
- A total of 1,022 patients were screened for BRAF mutations, resulting in 322 eligible patients (281 with BRAF V600E, 40 with BRAF V600K, and one with both mutations). One prior treatment (biologic or chemotherapy) was allowed; however, no prior treatment with a BRAF or MEK inhibitor was permitted. Patients were randomly assigned in a 2:1 ratio to receive trametinib (2 mg once daily) or IV chemotherapy (either DTIC 1,000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 every 3 weeks). Crossover for patients randomly assigned to chemotherapy was allowed; therefore, the primary endpoint was PFS.
- The investigator-assessed PFS was 4.8 months in patients receiving trametinib versus 1.5 months in the chemotherapy group (HR for PFS or death, 0.45; 95% CI, 0.33–0.63; P < .001). A radiology review blinded to treatment arm resulted in similar outcomes. Median OS has not been reached.
- Adverse events leading to dose interruptions occurred in 35% of patients in the trametinib group and 22% of those in the chemotherapy group. Adverse events leading to dose reductions occurred in 27% of patients receiving trametinib and 10% of those receiving chemotherapy.
- The most common adverse events included rash, diarrhea, nausea, vomiting, fatigue, peripheral edema, alopecia, hypertension, and constipation. Cardiomyopathy (7%), interstitial lung disease (2.4%), central serous retinopathy (<1%), and retinal-vein occlusion (<1%) are uncommon but serious adverse events associated with trametinib. On-study cutaneous SCCs were not observed. (Refer to the PDQ summaries on Supportive and Palliative Care for more information on coping with cancer.)
Resistance to BRAF inhibitors, in patients with BRAF V600 mutations, may be associated with reactivation of the MAPK pathway. Combinations of signal transduction inhibitors that block different sites in the same pathway or sites in multiple pathways are an active area of research.
Evidence (combination therapy with signal transduction inhibitors):
- In January 2014, the FDA granted accelerated approval to dabrafenib and trametinib in combination to treat patients with unresectable or metastatic melanomas who carry the BRAF V600E or V600K mutation as detected by an FDA-approved test. Accelerated approval was granted on the basis of objective response rates from an open-label phase II trial that randomly assigned 162 patients with unresectable or metastatic melanoma with the BRAF V600E or V600K mutation in a 1:1:1 ratio to receive dabrafenib alone (150 mg twice a day) or with trametinib (at a dose of either 1 mg or 2 mg twice a day). Patients who had disease progression on dabrafenib monotherapy could cross over to receive the combination of dabrafenib 150 mg plus trametinib 2 mg twice a day. Patients may have received one prior therapy other than a BRAF or MEK inhibitor.[Level of evidence: 1iiDiv].
- Patients treated with the combination had a response rate of 76%, with an average duration of 10.5 months. Patients treated with dabrafenib alone had a response rate of 54%, with an average duration of 5.6 months.
- The development of a new SCC of the skin associated with single-agent dabrafenib was reduced in the combination arm (19% with dabrafenib and 7% with the combination).
- The most frequent adverse events in the combination were pyrexia and chills, fatigue, nausea, vomiting, and diarrhea, although symptoms were rarely grade 3 or grade 4.
- In the combination group, 58% of patients required dose reductions because of adverse events, most associated with pyrexia. Re-escalation was possible in most patients.
- Rare, serious adverse events with the combination included decreased ejection fraction (<2%) and chorioretinopathy (<1%).
Full approval for the combination will depend on demonstration of improvements in PFS and survival from ongoing trials.
These early phase II data with combinations of BRAF and MEK inhibitors, in addition to the mechanistic understanding of pathways, have led to testing this combination in multiple phase III trials, such as NCT01584648, NCT01597908, and NCT01689519. Combination therapy to address other mechanisms of resistance (e.g., via activation of the PI3K/Akt pathway) are in early-phase trials.Multikinase inhibitors
The multikinase inhibitor sorafenib has activity against both the vascular endothelial growth-factor signaling and the Raf/MEK/ERK pathway at the level of RAF kinase.
This agent had minimal activity as a single agent in melanoma treatment. Two large, multicenter, placebo-controlled, randomized trials of carboplatin and paclitaxel plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[15,18]KIT inhibitors
Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[19-21] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.Chemotherapy
DTIC was approved in 1970 on the basis of overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[1,13,22-24] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, DTIC was shown to be inferior for OS.
Temozolomide (TMZ), an oral alkylating agent that hydrolyzes to the same active moiety as DTIC, appeared to be similar to DTIC (IV administration) in a randomized, phase III trial with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.
The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[22,25-27] Responses are usually short-lived, ranging from 3 to 6 months, although long-term remissions can occur in a limited number of patients who attain a CR.[25,27]
A randomized trial compared IV DTIC with TMZ, an oral agent; OS was 6.4 months for DTIC versus 7.7 months for TMZ (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between DTIC and TMZ, no benefit in survival has been demonstrated for either DTIC or TMZ; therefore, demonstration of similarity did not result in approval of TMZ by the FDA.[Level of evidence: 1iiA]
An extended schedule and escalated dose of TMZ was compared with DTIC in a multicenter trial randomly assigning 859 patients (EORTC-18032 [NCT00101218]). No improvement was seen in OS or PFS for the TMZ group, and this dose and schedule resulted in more toxicity than standard-dose, single-agent DTIC.[Level of evidence: 1iiA]
Two randomized, phase III trials in previously untreated patients with metastatic melanoma (resulting in FDA approval for vemurafenib  and ipilimumab ) included DTIC as the standard therapy arm. Both vemurafenib (in BRAF V600 mutant melanoma) and ipilimumab showed superior OS compared with DTIC in the two separate trials.
Attempts to develop combination regimens that incorporate chemotherapy (e.g., multiagent chemotherapy,[29,30] combinations of chemotherapy and tamoxifen,[31-33] and combinations of chemotherapy and immunotherapy [7,8,29,34-37]) have not demonstrated an improvement in OS.
A published data meta-analysis of 18 randomized trials (15 of which had survival information) that compared chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) reported no impact on OS.[Level of evidence:1iiA]Palliative local therapy
Melanoma metastatic to distant, lymph node–bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain may be palliated by resection, with occasional long-term survival.[35-37]
Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that symptom relief and some shrinkage of the tumor with radiation therapy may occur in patients with the following:[39,40]
- Multiple brain metastases.
- Bone metastases.
- Spinal cord compression.
The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. (Refer to the PDQ summary on Pain for more information.)
A phase I and II clinical trial (MCC-11543 [NCT00005615]) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma; results are pending.Treatment Options Under Clinical Evaluation for Unresectable Stage III, Stage IV, and Recurrent Melanoma
- Immunotherapy, single agent, and combination immunomodulation.
- Targeted therapy—single-agent and combination therapy.
- Signal transduction inhibitors, including P13K (phosphoinositide-3 kinase) and Akt (protein kinase B) inhibitors, CDK (cyclin-dependent kinase) in addition to BRAF and MEK.
- Antiangiogenesis agents. Preclinical data suggest that increased vascular endothelial growth factor production may be implicated in resistance to BRAF inhibitors.
- Targeted therapy for specific melanoma populations.
- In smaller subsets of melanoma, activating mutations may occur in NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (15%–20%), c-KIT (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), and CDK4 (cyclin-dependent kinase 4) (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target the pathways activated by these mutations are currently in clinical trials.
- Intralesional injections (for example, oncologic viruses).
- Complete surgical resection of all known disease versus best medical therapy.
- Isolated limb perfusion for unresectable extremity melanoma.
- Systemic therapy for unresectable disease.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III melanoma, stage IV melanoma and recurrent melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.References
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